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September 2022 "The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte

Here, we provide evidence that distal carboxyl-terminal tail (C-tail), but not proximal, phosphorylation site-directed mutagenesis and bioluminescence resonance energy transfer approaches that distal, not proximal, C-tail In addition, we show that GPCRs that have similarly positioned C-tail phosphoresidues are also able to However, although necessary for some GPCRs, we found that distal C-tail sites might not be sufficient In conclusion, this study provides evidence that distal C-tail phosphorylation sites specify GRK-βarrestin-mediated

October 2022 Coincident Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain management is a significant problem worldwide. The current frontline approach for pain-management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3), or selective inhibition of Gβγ regulation of PLCβ3, enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in HEK293 cells and found that MOR alone could not stimulate PLC, but rather required a coincident signal from a Gq coupled receptor. Knockout of PLCβ3, or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray (PAG) slices increased the potency of the selective MOR agonist DAMGO in inhibiting presynaptic GABA release. Finally, inhibition of Gq-GPCR coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately this could lead to identification of new non-MOR targets that would allow for lower dose utilization of opioid analgesics. " Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Newsletter HERE

2022 Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C activation of PKC and mutation of rat mGlu5a Ser901, a PKC-dependent phosphorylation site in the receptor C-tail

G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine-tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAMs tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface. Read full article

The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the

September 2022 "In the Wnt-β-catenin pathway, Wnt binding to Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6) co-receptors inhibits the degradation of the transcriptional coactivator β-catenin by recruiting the cytosolic effector Dishevelled (Dvl). Polymerization of Dvl at the plasma membrane recruits the β-catenin destruction complex, enabling the phosphorylation of LRP5/6, a key step in inhibiting β-catenin degradation. Using purified Fzd proteins reconstituted in lipid nanodiscs, we investigated the factors that promote the recruitment of Dvl to the plasma membrane. We found that the affinity of Fzd for Dvl was not affected by Wnt ligands, in contrast to other members of the GPCR superfamily for which the binding of extracellular ligands affects the affinity for downstream transducers. Instead, Fzd-Dvl binding was enhanced by increased concentration of the lipid PI(4,5)P2, which is generated by Dvl-associated lipid kinases in response to Wnt and which is required for LRP5/6 phosphorylation. Moreover, binding to Fzd did not promote Dvl DEP domain dimerization, which has been proposed to be required for signaling downstream of Fzd. Our findings suggest a positive feedback loop in which Wnt-stimulated local PI(4,5)P2 production enhances Dvl recruitment and further PI(4,5)P2 production to support Dvl polymerization, LRP5/6 phosphorylation, and β-catenin stabilization." Read more at the source #DrGPCR #GPCR #IndustryNews

Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. nematode Caenorhabditis elegans can also function independently of their seven-transmembrane domain and C Here, we show that Latrophilin-1 acts in trans to mediate morphogenesis of sensory structures in the C.

Affects Ca 2+ Sensing but Not G Protein Interaction "The calcium-sensing receptor is a homodimeric class C

Isabella Russell, Drs. A Perspective on Class C GPCR Based Genetically Encoded Biosensors Emergence of lumpy skin disease virus

Award: Pioneering GPCR-Driven Immunotherapies in Cancer Treatment Structure Therapeutics Appoints Angus C. Russell to Board of Directors Adiso Announces Groundbreaking Research Highlighting ADS024 a Novel Oral into GPCR Function Delineating the stepwise millisecond allosteric activation mechanism of the class C

September 2022 "Metabotropic γ-aminobutyric acid receptor (GABABR), a class C G protein-coupled receptor However, little is known about the mechanism for GP coupling and activation for class C GPCRs. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected

in the function of G protein-coupled receptors (GPCRs). βarrs typically interact with phosphorylated C-terminal tail (C tail) and transmembrane core (TM core) of GPCRs. However, the effects of the C tail- and TM core-mediated interactions on the conformational activation Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the C

C., Ring, A. ., Valant, C., Sexton, P. M., Christopoulos, A., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. C., Wess, J., & Kobilka, B. K. (2013). C. (2015). Structural biology.

C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4)

C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled receptor (GPCR), has one identified natural

Neuroscience Early pheromone perception remodels neurodevelopment and accelerates neurodegeneration in adult C. cell dysfunction and cancer immunotherapy failure Industry News X4 Pharmaceuticals Expected to Join Russell

This review will focus in particular on pepducins designed from protease-activated receptors, C-X-C motif

, et al. for their excellent work on Receptor determinants for ß-arrestin functional specificity at C-X-C D2-like and β2 adrenergic receptors Receptor determinants for ß-arrestin functional specificity at C-X-C

recombinant protein constructs GST-CB1414-472 and GST-CB1414-442 containing much of the human CB1 receptor C-terminal To this end we used three different antibodies, all raised against a peptide comprising the C-terminal

., Bennett, C. D., Rands, E., Diehl, R. E., Mumford, R. A., Slater, E. E., Sigal, I. S., Caron, M. J., & Strader, C. D. (1986). C., Lundin, L. G., & Schiöth, H. B. (2003).

dynamics underlying atypical chemokine receptor 3 activation Michael Trogdon, J Silvio Gutkind, Edward C on Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal -3 Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal

Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous

., the N-terminal and C-terminal fragments, seem to remain associated after self-proteolysis, as observed The recruitment likely requires the C-terminal PDZ-domain-binding motif of GPR125 and its interaction

Reference Araya, C. L., & Fowler, D. M. (2011). -P., Macdonald, C. B., Mehrotra, E., Patrick Rockefeller Grimes, Zahm, A. M., Trinidad, D. G., & Eckert, C. A. (2020). Predicting Drug Resistance Using Deep Mutational Scanning.

condition: Inactive β-arrestin in the cytosol spontaneously binds to the plasma membrane by inserting the C-edge Although this study has limitations, such as the absence of the flexible distal C-tail of βArr2 in the M., Medel-Lacruz, B., Baidya, M., Makarova, M., Mistry, R., Goulding, J., Drube, J., Hoffmann, C., Owen C., von Zastrow, M., Inoue, A., & Kobilka, B. K. (2022).

GPCR Activation and Signaling G protein activation via chemokine (C-X-C motif) receptor 4 and α1b -adrenoceptor

Gαi at specific residues within three strategic hotspots: the P loop, the interdomain cleft, and the C C Terminus (Tyr320): Phosphorylation at Tyr320 disrupted Gβγ binding, receptor coupling, and ligand-stimulated